The use of derivatives of 2,6-disubstituted phenols, such as 2,6-di-tert-butylphenols, as drugs is taught in the U.S. patents listed in Table 1. Their activity has been ascribed to inhibition of cyclooxidase (COX), or 5-lipooxygenase or leucotriene-oxidase. As anti-inflammatory drugs, they prevent, alleviate, cure, or are otherwise useful in treating animals, including humans, for pain, inflammatory disease, arthritic disease, rheumatoid arthritis, osteoarthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, periodontal disease, gingivitis, conjunctivitis, fever, and sunburn. As anti-viral drugs they prevent, alleviate, cure, or are otherwise they useful in treating hepatitis C, herpes, papilloma, warts, and other viral diseases. As anti-allergic drugs they prevent, alleviate, cure, or are otherwise useful in treating allergies, hay fever, poison ivy exposure, hypersensitivity, contact dermatitis, eczema, and asthma. As antilipidemics, they prevent, alleviate, cure, or are otherwise useful in treating atherosclerosis, high serum cholesterol, and cerebral stroke damage.
Nguyen U.S. Pat. No. 5,128,331 describes the lowering of plasma lipids and blood pressure by a di-phosphonate. The patents listed below in Table 1 disclose 2,6-di-substituted phenol-containing drugs and therapeutic uses. The papers listed below in Table 2 disclose anti-inflammatory 2,6-di-tert-butyl-4-(2-arylethenyl) phenols.
TABLE 1U.S.Pat. No.InventorAssigneeAction or effect4,029,812WagnerDow ChemicalHypolipidemic4,076,841WagnerDow ChemicalHypolipidemic4,078,084WagnerDow ChemicalHypolipidemic4,124,725MooreRiker LabsAnti-inflammatory4,172,082MooreRiker LabsAnti-inflammatory4,172,151MooreRiker LabsAnti-inflammatory4,212,882MooreRiker LabsAnti-inflammatory4,357,345MooreRiker LabsAnti-inflammatory4,414,217MooreRiker LabsAnti-inflammatory4,418,074MooreRiker LabsAnti-inflammatory4,431,831MooreRiker LabsAnti-inflammatory4,535,165MooreRiker LabsAnti-inflammatory4,568,696SmerbeckWarner LambertAnti-inflammatoryLeukotriene synthesisinhibitor,4,677,113BellRiker Labsantiallergic4,636,516KuboYamanouchiAntiarthritic4,708,966LoomansProcter & GambleAnti-inflammatory4,711,903MuellerG. D. Searle5-lipooxygenase inhibitor4,714,776BellRiker LabsAntiallergic4,755,524MuellerG. D. Searle5-lipooxygenase inhibitor4,833,155MuchowskiSyntexAnti-inflammatory4,835,190MuellerG. D. SearleAnti-inflammatory &antiallergy4,849,428DobsonProcter & GambleAnti-inflammatory4,857,588MuellerG. D. Searle5-lipooxygenase inhibitorAnti-inflammatory,4,906,662HashimotoOtsuka Pharmalipooxygenase inhibitor4,935,440MuchowskiSyntexAnti-inflammatory4,968,710RustadRiker LabsAntiallergic4,985,465HendlerAntiviralHypolipidemic,5,128,331NguyenSympharlowering of blood pressure5,143,928CetenkoWarner LambertAnti-inflammatory5,155,122ConnorWarner LambertAnti-inflammatory5,234,937CapirisWarner LambertAnti-inflammatory5,237,070ScherrerWarner LambertAnti-inflammatory5,248,682ConnorWarner LambertAnti-inflammatory5,256,680ConnorWarner LambertAnti-inflammatory5,280,045DobsonProcter & GambleAnti-inflammatory5,290,800CetenkoWarner LambertAnti-inflammatory5,298,514MuellerG. D. SearleAnti-inflammatory5,340,815ConnorWarner LambertAnti-inflammatory5,342,838MuellerG. D. SearleAnti-inflammatory5,347,036ScherrerRiker LabsAnti-inflammatory5,356,898BelliottiWarner LambertAnti-inflammatory,antioxidant5,376,670ConnorWarner LambertAnti-inflammatory5,487,893VachyFilecoAntiviral5,494,927CetenkoWarner LambertAnti-inflammatory5,495,043ScherrerRiker LabsAntiallergic5,498,745ScherrerRiker LabsAntiallergic5,510,361ScherzProcter & GambleAnti-inflammatory5,527,824ScherrerRiker LabsLeucotriene synthesaseinhibitor5,612,321NguyenHerculesAntiarthritic5,700,451YueProcter & GambleSunscreen5,709,847BissettProcter & GambleSunscreen5,804,572BlankProcter & GambleAnti-wrinkle, skinatrophy prevention5,849,732SuzukiTanabe SeiyakuAntioxidant preventingheart attacks5,942,530PanettaEli LillyPain treatment6,153,226VachyFilecoAntiviral6,218,437ChojkierU. CaliforniaAnti-hepatitis C6,348,493ChojkierU. CaliforniaAnti-hepatitis C6,369,097ChojkierU. CaliforniaAnti-hepatitis C6,420,428ChojkierU. CaliforniaAnti-hepatitis C
TABLE 2Lazer et al., J. Med. Chem, 1989, 32, pp. 100-104K. F. Swingle et al. In: “Anti-inflammatory and Anti-rheumatic Drugs”K. D. Rainsford, editor, CRC Press, 1985, pp. 105-126,“Anti-inflammatory activity of antioxidants”Moore & Swingle, Agents & Actions, 12 (5): 674-683 (1982)Hidaka et al. Ensho 3 (4): 511-512 (1983)Isomura et al., Chem. Pharm. Bull., 31 (9): 3168-3185 (1983)Isomura et al., Chem. Pharm. Bull., 32 (1): 152-165 (1984); Noda et al.,Kokai 80/15, 460Katsumi et al., “Pharmacological Properties of a New Anti-inflammatoryCompound, α-(3,5-di-tertbutyl-4-hydroxybenzylidene)-γ-butyrolactone(KME-4) and its Inhibitory Effects on Prostaglandin Synthetase and5-lipooxygenase, Jpn. J. Pharmacol. 36 (1), 77-85 (1984)VanDerGoot et al., European J. Medicinal Chem., 13 (5) 425-428Katayama et al., “In-vitro effect of N-methoxy-3-(3,5-ditert-butyl-4-hydroxy-benzylidene)-2-pyrrolidone (E-5110), a novel non-steroidal anti-inflammatory agent, on generation of some inflammatorymediators” Agents and Action, 21, 269-271 (1987)Lazer et al. “Effect of Structure on Potency and Selectivity in 2,6-Disubstituted 4-(2-Arylethenyl)-phenol Lipooxygenase Inhibitors J.Med. Chem. 33, 1982-1998 (1990).
The 2,6-disubstituted phenols, such as 2,6-di-tert-butylphenols are useful also as antioxidants and are used as stabilizing additives in plastics, elastomers, waxes and oils. Compound 1, the calcium salt of the monoethyl ester of (((3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)methyl) phosphonic acid, is an antioxidant sold, for example, by Ciba® Specialty Chemicals as Irganox® 1425. It is described by Ciba® Specialty Chemicals as a “highly efficient, non-discoloring stabilizer for organic substrates such as plastics, synthetic fibers, elastomers, adhesives, waxes, oils and fats. It protects these substrates against thermo-oxidative degradation. It is odorless, stable to light, and has excellent color retention. It has good compatibility with most substrates and high resistance to extraction” (by water or organic solvents). Furthermore, according to Ciba® Specialty Chemicals, Compound 1 imparts processing and good long term stability to polyolefins. It is particularly suitable for use in polypropylene fibers. Compound 1 is also an effective stabilizer for polyesters, crosslinked elastomers, specialty adhesives, and natural and synthetic tackifier resins and is additionally used as an esterification catalyst for the preparation of rosin esters. It is recommended for applications requiring improved extraction resistance, low volatility, excellent color and color stability and superior gas-fading resistance.” Its solubility in water is reported to be <0.01 weight %. In the rat, the oral LD50 of Compound 1 exceeds 6000 mg/kg and in the Chinese hamster it exceeds 2000 mg/kg. Its 4 hour inhalation at >2.35 mg/l air aerosol, with exposure to an aerosol comprising mostly (˜80%) particles smaller than 7 μm, resulted in no deaths of rats. Its intraperitoneal LD 50 in the rat is 662 mg/kg. No bioconcentration (accumulation) was detected in carp at 0.3-3 ppm.
